Project 1 Project Leader: Wong, Jeffrey Principal Investigator: RaubltSChek, Andrew DESCRIPTION: Clinical trials with ^Y-chimeric T84.66 anti-CEA demonstrate the feasibility and promise of combining radioimmunotherapy (RIT) with radiation-enhancing chemotherapy. Results indicate that clinically meaningful outcomes are achievable, with the greatest promise expected when RIT is integrated into other established therapies in the setting of small volume and subclinical disease. Results also show that the primary limitation of 90Y-cT84.66 is its immunogenicity, which limits the number of therapy cycles. Further refinements in the antibody and in how RIT is combined with other established therapies are therefore needed. To more effectively integrate RIT into established chemotherapy and radiotherapy regimens, the next generation of Phase I and II trials in Aim will focus on the most promising areas and evaluate strategies which: a) reduce the immunogenicity of the antibody, by utilizing a less immunogenic humanized version of T84.66; b) integrate RIT into established, active chemotherapy and radiation/chemotherapy regimens and therefore optimize the clinical impact of the additional pr^artial Hdro\os[unreadable]es> fo\f mrardi\ia^tiro\n t/o\ +tui m\rro\rr\r aQc/h*hieiav\a/abHleI^ wlAiti+hH **Y^V-_T8~Q4^.6R6R;[unreadable]aonrtdH c/N) \ttreoaott nr*or\n-fc*lhne[unreadable]*mrYo\f\-re&frao/c^t+ortri'vw, somaolll v%o/rltuli mimea disease, where the tumor uptake of radiolabeled antibody is expected to be the highest and the clinical impact the greatest. Clinical trials will evaluate 1) RIT as an additional component of front-line multi-agent chemotherapy in colorectal cancer patients with newly diagnosed metastatic disease; 2) RIT as an added component to hepatic arterial chemotherapy in colorectal cancer patients after disease resection who are at high risk of subclinical, occult regional and distant metastases; and 3) RIT as an additional therapy integrated into an established radiation and chemotherapy regimen for CEA+ locally advanced, surgically un-resectable non-small cell lung cancer, who are at high risk of local and distant recurrence despite conventional therapies. These trials will also provide the unique opportunity to evaluate the effects of the anti-angiogenesis antibody, bevacizumab, on 90Y-T84.66 tumor uptake, to assess tumor targeting and pharmacokinetics of iriln-bevacizumab and to ultimately assess its potential as a candidate antibody for RIT. Trials in Aim 2 will evaluate RIT directed against HER2 in breast cancer. At this institution, trastuzumab, radiolabeled with 111ln, has demonstrated tumor targeting and organ dosimetry comparable to cT84.66, justifying its evaluation in a phase I therapy trial labeled with 90Y. This will be followed by a phase I trial which integrates Y-trastuzumab RIT into an established chemotherapy regimen in patients with metastatic breast cancer. Trastuzumab has properties that make it attractive for RIT due to its anti-tumor effects, radiation/chemotherapy enhancing effects, and minimal immunogenicity.